Effects of quinidine on ventricular repolarization

The possibility that an asynchronous increase in the ventricularmonophasic action potential duration is the basis of the quinidine-inducedtorsade de pointes, has led us to study the electrophysiologicaleffects of increasing doses of intravenous quinidine. We measuredthe monophasic action potential duration and the ventriculareffective refractory period at several right ventricular myocardialsites in the anaesthetized dog.Our results showed that quinidineinduces a dose-dependent prolongation in ventricular effectiverefractory period and in ventricular monophasic action potentialduration. These increases were uniform throughout the rightventricle. No variations in repolarization or in refractorinesswere observed between the four ventricular sites studied.Theresults suggest that quinidine does not have a direct effecton dispersion of repolarization, and that mechanisms other thanits direct electrophysiological action are involved in the developmentof torsade de pointes.     

Effects of the class III antiarrhythmic drug dofetilide on ventricular monophasic action potential duration and QT interval dispersion in stable angina pectoris.

The effects of intravenous dofetilide on ventricular monophasic action potential duration and effective refractory period at the right ventricular apex and outflow tract were studied in 18 patients (aged 37 to 70 years) with ischemic heart disease. Six patients received low-dose dofetilide as a 3 micrograms/kg loading dose over 15 minutes and a 1.5 micrograms/kg maintenance dose over 45 minutes; 6 received high-dose dofetilide 6 + 3 micrograms/kg and 6 placebo. During atrial pacing at a cycle length of 800 ms high-dose dofetilide prolonged right ventricular apex monophasic action potential duration by 45 ms (16%) and the effective refractory period by 40 ms (16%). At the right ventricular outflow tract, monophasic action potential duration was prolonged by 45 ms (15%) and effective refractory period by 55 ms (21%). During atrial pacing at a cycle length of 500 ms high-dose dofetilide prolonged the right ventricular apex monophasic action potential duration by 40 ms (18%) and the effective refractory period by 43 ms (21%). The right ventricular outflow tract monophasic action potential duration was prolonged by 33 ms (14%) and effective refractory period by 45 ms (21%). Dofetilide produced no increase in the dispersion of repolarization between the 2 sites. During the maintenance infusion QTc prolongation by high-dose dofetilide averaged 43 ms (10%) with no increase of interlead QT dispersion. The effects of dofetilide on QT interval and effective refractory period are shown to be due to a direct effect on action potential duration with no effect on dispersion. No rate dependence of monophasic action potential prolongation was detected at these cycle lengths.     

Prolongation of the human cardiac monophasic action potential by sotalol

Sotalol and propranolol are nonselective beta-adrenergic blocking agents. Sotalol at low concentration, unlike propranolol, prolongs the duration of the transmembrane action potential. In a double-blind study, the electrophysiologic effects of intravenous sotalol (0.30 or 0.60 mg/kg; n = 9) were compared with intravenous propranolol (0.15 or 0.20 mg/kg; n = 8) in 17 patients with use of bipolar suction electrodes in the right atrium and right ventricle to determine whether sotalol prolongs the monophasic action potential duration in man. After administration of sotalol, there were significant increases (paired t test) in the Q-T interval (p less than 0.001), right atrial effective refractory period (p less than 0.05), right ventricular effective refractory period (p less than 0.005), right atrial monophasic action potential duration at 90% repolarization (p less than 0.01), and right ventricular monophasic action potential duration at 90% repolarization (p less than 0.005). Prolongation of the monophasic action potential duration was dependent on plasma sotalol concentration. There were no significant changes in these variables after propranolol. The spontaneous cycle length and Wenckebach cycle length increased significantly in both groups, and the mean blood pressure decreased in both, although not significantly after propranolol. In summary, sotalol but not propranolol prolonged atrial and ventricular effective refractory periods and lengthened the monophasic action potential and the Q-T interval of human myocardium after intravenous infusion. The ability to acutely prolong repolarization at therapeutic plasma concentration is unique among known competitive beta-adrenergic receptor antagonists.     

Signed value of monophasic action potential duration difference: A useful measure in evaluation of dispersion of repolarization in patients with ventricular arrhythmias

AIMS: To evaluate the usefulness of the signed value of monophasicaction potential duration difference in analysing the causeof dispersion of ventricular repolarization. METHODS AND RESULTS: Monophasic action potentials were simultaneously recorded fromthe right ventricular apex and outflow tract during programmedstimulation in 36 patients with ventricular arrhythmias. Thetime difference between the ends of repolarization on the twomonophasic action potentials was used as a measure of the dispersionof ventricular repolarization, and the signed value of the monophasicaction potential duration difference was used to specify thecontributions of the activation time difference and the monophasicaction potential duration difference to the dispersion of ventricularrepolarization. During right ventricular pacing, single anddouble programmed stimulation and at the induction of ventriculararrhythmias, the dispersion of ventricular repolarization andthe signed value of monophasic action potential duration differencewere markedly greater in the 11 patients with polymorphic ventriculartachycardia/ventricular fibrillation induced than in the 13patients with monomorphic ventricular tachycardia induced, andin the 10 patients with clinical polymorphic ventricular tachycardia/ventricularfibrillation/cardiac arrest than in the 12 patients with sustainedmonomorphic ventricular tachycardia. This disclosed that theincreased dispersion of ventricular repolarization was causedby increases in both the activation time difference and themonophasic action potential duration difference in the former,but mainly by an increased activation time difference in thelatter groups. CONCLUSION: The signed value of monophasic action potential duration differencecan specify whether an increased dispersion of ventricular repolarizationis caused by in-homogeneous repolarization, inhomogeneous conductionor both, and thereby it is useful in study of the mechanismof ventricular arrhythmias.     

Induction of Ventricular Fibrillation by T Wave Shocks: Observations from Monophasic Action Potential Recordings

Introduction: Shocks given during the vulnerable period of cardiac repolarization may induce ventricular fibrillation (VF). However, the relationship of the vulnerable period and the monophasic action potential (MAP) has not yet been reported in humans. The purpose of this study was, therefore, to determine how the monophasic action potential recorded from the right ventricle correlates with inducibility of VF using T wave shocks during ventricular pacing.Methods: Eleven patients undergoing implantable cardioverter defibrillator (ICD) implantation had a MAP catheter positioned in the right ventricle (RV). The local monophasic action potential duration at 90% repolarization (MAP90) duration was measured during pacing at 400 ms. VF induction was attempted by pacing at 400 ms for 10 cycles and then giving a 1.0 joule monophasic T wave shock at varying coupling intervals (CI) to the last paced stimulus. The maximum and minimum CI that induced VF were determined and mapped in relation to the MAP90 recording.Results: The average paced MAP duration was 275 ± 20ms. The minimum and maximum CI to induce VF were 255 ± 24ms and 325 ± 36ms respectively. This ranged from 93% to 118% of the MAP90 duration but because of delay in conduction time to the MAP catheter, shocks that induced ventricular fibrillation occurred between 74% and 99% of local repolarization time.Conclusion: VF is inducible with low energy T wave shocks falling during the last 25% of the right ventricular MAP90 recording. This corresponds with VF initiation during phase III repolarization.     

Reduction of dispersion of repolarization and prolongation of postrepolarization refractoriness explain the antiarrhythmic effects of quinidine in a model of short QT syndrome

Background: Short QT syndrome (SQTS) is a newly described ion channelopathy, characterized by a short QT interval resulting from an accelerated cardiac repolarization, associated with syncope, atrial fibrillation, and sudden cardiac death due to ventricular fibrillation. As therapeutic options in SQTS are still controversial, we examined antiarrhythmic mechanisms in an experimental model of SQTS. Methods and Results: Pinacidil, an I_K‐ATP channel opener, was administered in increasing concentrations (50–100 μM) in 48 Langendorff‐perfused rabbit hearts and led to a significant reduction of action potential duration and QT interval, thereby mimicking SQTS. Eight simultaneously recorded monophasic action potentials demonstrated an increase in dispersion of repolarization, especially between the left and the right ventricle. During programmed ventricular stimulation with up to two extrastimuli, pinacidil significantly increased the inducibility of ventricular fibrillation (1 heart under baseline conditions, 29 hearts during pinacidil administration; P = 0.0001). Additional treatment with the I_Kr blocker sotalol (100 μM) and the class I antiarrhythmic drugs flecainide (2 μM) and quinidine (0.5 μM) randomly assigned to three groups of 16 hearts led to prolongation of repolarization as well as refractory period. Sotalol or flecainide did not reduce the rate of inducibility of ventricular fibrillation significantly (P = 0.63; P = 0.219). However, quinidine reduced the inducibility of ventricular fibrillation by 73% (P = 0.008). The antiarrhythmic potential of quinidine was associated with a significantly greater prolongation of MAP duration, refractoriness, and postrepolarization refractoriness (PRR) as compared with sotalol and flecainide. Moreover, quinidine, in contrast to sotalol and flecainide, reduced dispersion of repolarization. Conclusion: Pinacidil mimics SQTS via increasing potassium outward currents, thereby facilitating inducibility of ventricular fibrillation. Quinidine demonstrates superior antiarrhythmic properties in the treatment of ventricular fibrillation in this model as compared with sotalol and flecainide because of its effects on refractoriness, PRR, and by reducing dispersion of repolarization.     

Frequency-dependent effects of quinidine on the ventricular action potential and QRS duration in humans

We studied the frequency-dependent effects of quinidine on the right ventricular action potential and QRS duration in 10 patients (nine men and one woman; mean age, 57 +/- 14 years) undergoing electrophysiologic studies for clinical indications. The right ventricular monophasic action potential, electrocardiographic, and conventional intracardiac electrical signals from various sites were recorded at different pacing cycle lengths from 30 seconds to 1 minute before and after a 10-mg/kg i.v. quinidine infusion. We used the extrastimulus technique to determine the effects of quinidine on ventricular refractory periods at different pacing cycle lengths and on the abrupt changes of the action potential duration. The action potential duration progressively decreased as the ventricular pacing rate increased at baseline and after quinidine infusion. Quinidine significantly increased the action potential duration from that of control by 25 msec (p less than 0.02) at the relatively slow pacing cycle lengths of 600, 500, and 400 msec. Quinidine's effect on the action potential duration was attenuated at the pacing cycle length of 350 msec and became negligible at 300 msec. In contrast, quinidine progressively lengthened the QRS duration as the pacing rate increased (20, 18, 37, 46, and 34 msec at pacing cycle lengths of 600, 500, 400, 350, and 300 msec, respectively; p less than 0.05). There were no rate-dependent changes in the QRS duration during the control period. The relation between the ventricular refractory periods and the action potential duration at different pacing cycle lengths was also determined before and after quinidine infusion.(ABSTRACT TRUNCATED AT 250 WORDS)     

Changes in myocardial repolarization in patients undergoing balloon valvuloplasty for congenital pulmonary stenosis: evidence for contraction-excitation feedback in humans

Alterations in ventricular loading conditions lead to changes in action potential duration and arrhythmias via contraction-excitation feedback; a decrease in load leads to prolongation of repolarization. To determine whether changes in right ventricular load alter ventricular repolarization in man, the corrected QT interval, a measure of overall ventricular repolarization, was measured in 32 patients before and after valvuloplasty for pulmonary stenosis. Right ventricular systolic pressure decreased (82.5 +/- 30.7 to 40.5 +/- 9.5 mm Hg, p less than .001) and the QTc increased concurrently (409.1 +/- 24.3 to 440.7 +/- 28.0 msec, p less than .001) after successful valvuloplasty. The increase in QTc was most marked for those patients with a greater than 30 mm Hg decrease in right ventricular pressure (40.0 +/- 23.3 vs 16.3 +/- 21.3 msec, p = .006). In a subset of seven patients in whom monophasic action potentials were recorded, monophasic action potential duration, a measure of local repolarization, was prolonged (230.0 +/- 24.3 vs 216.9 +/- 21.9, p less than .001) after successful valvuloplasty, confirming that the QTc prolongation reflected changes in local ventricular repolarization. In addition, during nine acute right ventricular outflow tract occlusions in a subset of six patients, monophasic action potential duration shortened (206.6 +/- 17.6 vs 221.7 +/- 20.9 msec, p less than .01) and early afterdepolarizations developed consistent with contraction-excitation feedback. These data suggest that, in humans, changes in mechanical load are associated with changes in ventricular repolarization consistent with contraction-excitation feedback.     

硫酸镁对家兔在体心脏跨室壁心肌复极不均一性的影响

目的：观察静脉注射索他洛尔后，硫酸镁对家兔跨室壁心肌复极不均一性的影响，探讨其治疗室性心律失常的机制。方法：采用单相动作电位（monophasic action potential,MAP)记录技术，同步记录12只开胸兔左室心外膜心肌、中层心肌和心内膜心肌的MAP，在静脉注射索他洛尔基础上，静脉滴注硫酸镁后观察其对心肌得极不均一性的影响。结果：（1）索他洛尔剂量依赖性地显延长中层心肌的MAP复极100％时程，增加跨室壁复极离散度（transmural dispersion of repolarization,TDR)；静脉滴注硫酸镁后TDR明显减少。（2）索他洛尔剂量依赖性地诱发早期后除极（early afterdepolarization,EAD)和尖端扭转型室性心动过速（torsade de pointes,TdP)的发生率；硫酸镁抑制索他洛尔诱导的EAD和TdP。结论：硫酸镁逆转索他洛尔所致的TDR增加，抑制索他洛尔诱导产生EAD，其治疗TdP的机制可能与此有关。     

Frequency-dependent effects of quinidine on the relationship between action potential duration and refractoriness in the canine heart in situ

To determine the normal relationship in vivo between action potential duration (APD) and effective refractory period (ERP) over a large range of steady-state cycle lengths (CLs) and to determine how a sodium channel-blocking agent, quinidine, affects this relationship, we developed a new contact electrode technique for simultaneous measurements of monophasic action potentials and refractoriness at a single site in the beating heart in situ. Recordings were made from left ventricular epicardium in open-chest dogs during steady-state pacing at CLs from 220 to 600 msec both before and after therapeutic intravenous administration of quinidine. During baseline both APD at 90% repolarization (APD90) and ERP were linearly correlated to CL with nearly identical slopes: y = 0.24x CL + 83.0 (r = 1.0; p less than .0001) for APD90 and y = 0.22x CL + 82.3 (r = 1.0; p less than .0001) for ERP. Expressed in percent repolarization, ERP coincided with a repolarization level of 79% to 83%, with no appreciable influence of CL on this relationship. Quinidine increased APD90 by a small but significant amount (8 to 12 msec), which was independent of CL. In contrast, the effect on ERP of quinidine exhibited marked frequency dependence (p less than .0002), producing progressively greater ERP increase at shorter CLs, as compared with both baseline ERP and concomitant APD90. The duration by which ERP exceeded APD90 reached 44 +/- 14 msec at a CL of 220 msec.(ABSTRACT TRUNCATED AT 250 WORDS)     

Quinidine-induced long QTU interval and torsade de pointes: role of bradycardia-dependent early afterdepolarizations

Right ventricular endocardial monophasic action potential recordings were obtained in a patient with a qunidine-induced long QTU interval and polymorphic ventricular tachycardia of the torsade de pointes type. The recording showed a deflection on phase 3 repolarization characteristic of early afterdepolarization. The early afterdepolarization was synchronous with the U wave in surface electrocardiographic leads and there was a strong correlation between the amplitude of both waves. A strong correlation was also present between the cardiac cycle length and the U wave amplitude with larger amplitudes after longer cycles. Ventricular ectopic beats occurred only after long cycle lengths and seemed to arise close to the peak of the U wave and early afterdepolarization. However, there was no correlation between the amplitude of the U wave or early afterdepolarization and the occurrence of ectopic beats. Rapid ventricular pacing resulted in suppression of the ectopic rhythm associated with suppression of both the U wave and the early afterdepolarization. This case provides the first evidence to suggest that a quinidine-induced long QTU interval and torsade de pointes may be related to bradycardia-dependent early afterdepolarizations, although other factors may be involved in triggering the arrhythmia.     

Atrial-specific drug AVE0118 is free of torsades de pointes in anesthetized dogs with chronic complete atrioventricular block

BACKGROUND: The novel compound AVE0118 has been shown to prevent and terminate persistent atrial fibrillation. AVE0118 blocks I(Kur), I(KAch), and I(to), leading to prolongation of atrial repolarization with no change in ventricular repolarization. This finding suggests that AVE0118 may be devoid of proarrhythmic side effects. Experimentally, AVE0118 has been antiarrhythmic against some specific ventricular arrhythmias. OBJECTIVES: The purpose of this study was to investigate the proarrhythmic and antiarrhythmic effects of AVE0118 in anesthetized dogs with chronic complete AV block, known for a high proclivity for torsades de pointes (TdP). METHODS: AVE0118 was administered intravenously as a fast infusion (0.5 mg/kg/5 min) and a slow infusion (3 or 10 mg/kg/60 min). Dofetilide was given to induce TdP. ECG and monophasic action potentials were recorded. Short-term beat-to-beat variability (STV) of the left ventricular monophasic action potential duration (MAPD) was calculated. We examined whether AVE0118 (1) caused ventricular proarrhythmia (both infusions), (2) prevented dofetilide-induced TdP (slow infusion + dofetilide after 30 minutes), and (3) abolished TdP (fast infusion). RESULTS: At 0.55 +/- 0.10 microg/mL (fast infusion at 10 minutes), AVE0118 did not increase ventricular repolarization or induce TdP; however, right atrial MAPD(50) and MAPD(90) were significantly increased by 26% +/- 9% and 10% +/- 5%, respectively (P <.05 vs baseline). At 1.9 +/- 0.5 microg/mL and 6.1 +/- 1.2 microg/mL (30 minutes of 3 or 10 mg/kg/h), AVE0118 did not induce TdP (0/6 and 0/4) nor prevent dofetilide-induced TdP (6/6 and 2/2). Dofetilide significantly increased all repolarization parameters, including STV from 2.1 +/- 0.4 ms to 4.6 +/- 1.8 ms (P <.05 vs baseline), which were not changed by AVE0118 (to 2.1 +/- 0.3 ms after 30 minutes). Rapid infusion of AVE0118 did not suppress dofetilide-induced TdP. CONCLUSION: In the anesthetized chronic complete AV block dog, the atrial-specific drug AVE0118 is free of TdP and has no antiarrhythmic properties against dofetilide-induced torsades de pointes.     

Detection of proarrhythmia in the female rabbit heart: blinded validation

INTRODUCTION: Reliable detection of drug-induced proarrhythmia, especially the potential for polymorphic ventricular tachycardia, is of great importance in the development of new compounds that are safe for the heart and was evaluated in a blinded study. METHODS AND RESULTS: In 142 female rabbits, the monophasic action potential was used to determine intraventricular conduction, action potential duration (APD), triangulation (APD30 to APD90), reverse use-dependence, instability and presence of chaotic behavior, early afterdepolarizations, torsades de pointes (TdP), and ventricular fibrillation. In addition, 31 coded drugs were tested in a blinded fashion in another 150 hearts. Prototype cardiovascular agents [quinidine (IA), lidocaine (IB), flecainide (IC), propranolol (II), sotalol (IIIB), amiodarone (IIIAB) and verapamil (IV)] were correctly characterized in terms of their effects upon conduction and APD. Agents documented in clinical practice to have proarrhythmic potential (droperidol, sotalol, mibefradil, bepridil, lidoflazine, ketanserin, sertindole, terfenadine, haloperidol, astemizole, cisapride, ziprasidone, lubeluzole, dofetilide, quinidine, ibutilide) were identified as such. Pimozide is reported to rarely produce TdP and was also found to elicit Class III action with few adverse effects. Equally important, agents believed not to be proarrhythmic (two solvents, atenolol, propranolol, fenoximone, cetirizine, verapamil, sildenafil, lidocaine, diltiazem) were identified as having no proarrhythmic activity. CONCLUSION: The SCREENIT method properly characterized and quantified prototype cardiovascular drugs and correctly identified proarrhythmic noncardiovascular agents of various mechanisms, but it did not produce false-positive results.     

Electrophysiological effects of left ventricular hypertrophy. Effect of calcium and potassium channel blockade.

BACKGROUND. To define the arrhythmogenic effects of left ventricular hypertrophy (LVH) in the intact heart, we carried out a detailed electrophysiological assessment in our previously validated feline aortic-banding model and then tested the effects of agents that blocked either the slow inward calcium or voltage-dependent potassium channel. METHODS AND RESULTS. We measured intraventricular and interventricular conduction times, excitability thresholds, ventricular effective refractory periods, and monophasic action potential duration at several sites in cats with LVH as well as in concurrent control (sham-operated) cats. In addition, we assessed vulnerability to ventricular arrhythmia using direct measurement of ventricular fibrillation (VF) thresholds and by standard techniques of programmed stimulation. Despite finding no difference between LVH and sham-operated cats in mean values for several electrophysiological parameters, the former group was significantly more vulnerable to VF, with more spontaneous VF and lower VF thresholds. Compared with the sham controls, LVH cats also had a greater dispersion of effective refractory period (35 +/- 11 versus 12 +/- 4 msec, p less than 0.01) and monophasic action potential duration at 90% repolarization (69 +/- 25 versus 39 +/- 7 msec, p less than 0.02). Verapamil had no significant effect on these electrophysiological parameters, nor did it affect VF threshold. However, risotilide, an inhibitor of the voltage-dependent potassium channel, narrowed dispersion of the effective refractory period and monophasic action potential duration concomitant with a marked reduction in ventricular vulnerability. CONCLUSIONS. LVH has a pronounced effect on dispersion of refractoriness and repolarization and renders the ventricle more vulnerable to fibrillation. Blockade of the voltage-dependent potassium channel, but not the slow inward calcium channel, narrows the dispersion of recovery of excitability and protects against VF.     

Influences of catecholamines on the sudden death induced in dogs by an antifungal agent, D0870

We previously reported the occurrence of QT prolongation and sudden death owing to torsades de pointes (TdP) in dogs treated with D0870, an antifungal agent. In the present study, we evaluated the influences of epinephrine and isoproterenol on the onset of TdP each time D0870 was given to 6 anesthetized open-chest dogs at a dosage of 20 mg/kg, 5 times every 40 minutes, by the simultaneous measurements of surface electrocardiogram and epicardial monophasic action potential (MAP). D0870 alone induced noticeable prolongation of the QT interval and action potential duration (APD), but neither ventricular premature contraction (VPC) nor sudden death. In contrast, the additional administration of the catecholamines induced a greater shortening of APD during the later phase of repolarization than during its earlier one and VPCs in all dogs tested, and sudden deaths owing to TdPs in 4 of the 6 dogs treated with D0870. These results suggest that D0870 alone does not induce TdP but that catecholamines play an important part in the development of sudden death induced by D0870 in dogs.     

L-type calcium current recovery versus ventricular repolarization: preserved membrane-stabilizing mechanism for different QT intervals across species

BACKGROUND: Long QT syndrome is associated with early after-depolarization (EAD) that may result in torsade de pointes (TdP). Interestingly, the corrected QT interval seems to be proportional to body mass across species under physiologic conditions. OBJECTIVE: The purpose of this study was to test whether recovery of L-type calcium current (I(Ca,L)), the primary charge carrier for EADs, from its inactivated state matches ventricular repolarization time and whether impairment of this relationship leads to development of EAD and TdP. METHODS: Transmembrane action potentials from the epicardium, endocardium, or subendocardium were recorded simultaneously with a transmural ECG in arterially perfused left ventricular wedges isolated from cow, dog, rabbit, and guinea pig hearts. I(Ca,L) recovery was examined using action potential stimulation in isolated left ventricular myocytes. RESULTS: The ventricular repolarization time (action potential duration at 90% repolarization [APD(90)]), ranging from 194.7 +/- 1.8 ms in guinea pig to 370.2 +/- 9.9 ms in cows, was linearly related to the thickness of the left ventricular wall among the species studied. The time constants (tau) of I(Ca,L) recovery were proportional to APD(90), making the ratios of tau to APD(90) fall into a relatively narrow range among these species despite markedly different ventricular repolarization time. Drugs with risk for TdP in humans were shown to impair this intrinsic balance by either prolongation of the repolarization time and/or acceleration of I(Ca,L) recovery, leading to the appearance of EADs capable of initiating TdP. CONCLUSION: An adequate balance between I(Ca,L) recovery and ventricular repolarization serves as a "physiologic stabilizer" of ventricular action potentials in repolarization phases.     

Immediate quantitation of antiarrhythmic drug effect by monophasic action potential recording in coronary artery disease

A contact electrode catheter, which permits clinical recording of cardiac monophasic action potentials (MAPs), was used as a means of quantifying the electrophysiologic effect of 2 antiarrhythmic drugs, procainamide and quinidine. MAP recordings were made in continuous fashion from the right ventricle in 16 patients, before and after the intravenous administration of procainamide (11 patients) or quinidine (5). Increases in the MAP duration at 90% repolarization (MAPD90) were used as indexes of drug effect and related to plasma drug level. Surface electrocardiographic (QRS duration, corrected QT interval [QTC]) and electrophysiologic (ventricular effective refractory period) measurements, in addition to MAPD90, were made at the same time as blood sampling for plasma drug level determination. Dose response curves, plotting change in MAPD90 versus plasma drug level, showed strong linear correlation for both procainamide (p less than 0.0001) and quinidine (p less than 0.0001). The variance (error of estimation) of the predictive relation, change in MAPD90 versus plasma drug level, was significantly lower than that of change in QTC (p less than 0.001), QRS duration (p less than 0.0001) or ventricular effective refractory period (p less than 0.0001) versus plasma drug level for both procainamide and quinidine. Changes in MAP duration closely correlate with plasma drug level, and as such, may serve as an immediate, quantitative indicator of myocardial drug effect during the administration of antiarrhythmic agents.     

Pauses after burst pacing provoke afterdepolarizations and torsades de pointes in a patient with long QT syndrome

A patient with long QT syndrome and syncope underwent electrophysiological testing and recording of monophasic action potentials (MAP). Programmed ventricular stimulation using up to three premature stimuli did not provoke arrhythmias. Transient action potential prolongation and afterdepolarizations were observed during pauses directly after high-rate fix frequent right ventricular burst pacing at 120-160 bpm. During the pause after burst pacing at 180 bpm, afterdepolarizations at 16-19% amplitude of the MAP plateau persisted for several beats and preceded a short episode of torsades de pointes. High-rate burst pacing provoked afterdepolarizations and triggered torsades de pointes in this patient with long QT syndrome.     

Clinical value of monophasic action potentials

The method of monophasic action potential (MAP) recording has experienced a significant surge in interest since the introduction of the contact electrode, which in contrast to the suction electrode, allows the safe and simple use of this technique in the clinical electrophysiology laboratory. MAP recording not only provide for a more precise determination of local activation, but most importantly, permit direct measurement of myocardial repolarization and action potential duration (APD), respectively. This had led to new insights into the cycle-length-dependence of the human APD, both in response to single extrastimuli and to steady-state heart rate changes. An advancement of the contact electrode catheter design now permits simultaneous pacing and MAP recording, and thereby, simultaneous determinations of APD and effective refractory periods (EPP) at the same endocardial site in the human heart. MAP recordings have demonstrated significant usefulness in the direct monitoring of antiarrhythmic drug effects, both in terms of dosage control and in the direct measurement of antiarrhythmic drug effects on the relationship between ERP and APD (ERP/ARD-ratio). Because MAP recordings reflect the local cellular electrophysiology, they also provide a more sensitive and precise index of myocardial ischemia than conventional ECG recordings. This can be utilized to assess the success of revascularizing procedures directly during or after the intervention. Recently, MAP recordings helped to discover early after-depolarizations in patients with "torsade de pointes", providing a possible explanation for the mechanism of polymorphous ventricular tachycardia in man.